Loss of healthy cardiac tissue leads to heart failure that gravely affects quality of life and causes high mortality rates. Studies in animal models and clinical trials have shown that transplanted stem cells can aid cardiac recovery, offering new hope to millions of patients. Recent evidence for resident cardiovascular stem cells in the adult heart has raised expectations that these cells may be harvested or engaged in situ to heal injured myocardium. However, the biological properties of cardiovascular stem cells are poorly understood impeding the development of new therapies. To address this problem, the Vanderbilt University Consortium proposes three interacting projects (P1-P3) supported by an animal models and histology Core. P1 will focus on the isolation and characterization of adult cardiac progenitor cells and study their role in organ homeostasis and ischemic injury using transgenic mice with fluorescently tagged stem cells. Moreover, in collaboration with P2, P1 will test pro-cardiogenic molecules for their ability to enhance the repair capacity of endogenous cardiac progenitor cells in a myocardial infarction mouse model. Using genetically engineered embryonic stem cells, P2 will isolate and characterize endocardial progenitor cells and analyze their regenerative potential. P2, in collaboration with P1 will also test whether combinatorial therapy with both endocardial and myocardial progenitor cells will provide significant improvement in myocardial performance over transplantation of single progenitor cell populations. P3 will investigate the effects of disease conditions on the fate of transplanted and endogenous cardiovascular progenitor cells in collaboration with P1 and P2. To this end, P3 will determine how myocardial fibrosis, circulating inflammatory cytokines and oxidant stress inherent to heart failure impede the action of progenitor cells and myocardial regeneration. To standardize experimental approaches and readouts of cardiac output, the consortium includes a "Mouse Cardiovascular Surgery and Pathophysiology Core" to provide: a) mouse models of myocardial injury in conjunction with cell transplantation;and, b) rapid and comprehensive assessment of cardiac histology, function and structure with sophisticated imaging techniques. The proposed consortium will create a dynamic network of investigators to advance our knowledge in the biology of cardiovascular progenitor cells and their role in cardiac tissue repair. Next to generating important new mechanistic insights towards optimizing key steps in the cardiac regeneration process, emphasis is placed on practical studies in pre-clinical settings for rapid translation to clinical therapy.